The objective of this project is to study the effects of p-methoxyamphetamines (PMA) and other methoxyamphetamines on brain serotonin and catecholamines. I have obtained biochemical and pharmacological evidence that PMA selectively increases the release and blocks the uptake of serotonin. These data demonstrate that PMA releases serotonin from central nervous tissues both in vivo and in vitro, thus indicating that this increased release of brain serotonin by PMA appears not to be attributable to an inhibition of the reuptake mechanism. Chlorimipramine, a selective serotonin uptake inhibitor, blocked the increased release of serotonin induced by PMA and the PMA-induced behavioral responses, e.g., disruption of fixed ratio responding, increased myoclonic twitch activity (MTA) of suprahyoideal muscle and increased locomotor activity. The results indicated that chlorimipramine blocks the effects of PMA by preventing the release of serotonin by PMA in the CNS. Studies with PMA and 2,5-DMA on the MTA indicated that whereas PMA activated the MTA by indirectly releasing serotonin, 2,5-DMA elicited its pharmacologic effect by directly acting on serotonin receptors. We also studied the relationship between receptor binding activity and the level of neurotransmitter in the serotonergic system. The serotonergic receptor activity was monitored by measuring the binding of 3H-serotonin to the cell membrane fraction. P-chlorophenylalanine (PCPA), caused a time- and dose-dependent increase in specific 3H-serotonin binding to the brain P3 fraction. The increased 3H-serotonin binding elicited by PCPA was antagonized by 5-HTP and pargyline. These results indicate that the modulation of brain serotonin levels can have profound effects on the specific 3H-serotonin binding activity measured in rat brain.